Imidazopyridine intermediates

ABSTRACT

The invention relates to compounds of the formula 1, 
                         
in which the substituents and symbols have the meanings indicated in the description. The compounds are valuable intermediates for the preparation of pharmaceutical active compounds.

TECHNICAL FIELD

The invention relates to novel compounds which are used in thepharmaceutical industry as valuable intermediates for the preparation ofactive compounds.

PRIOR ART

The international patent applications WO 98/54188, WO 01/72756, WO01/72754, WO 01/72755, WO 01/72757, WO 02/34749, WO 03/016310, WO03/014120 and WO 03/014123 disclose tricyclic imidazopyridinederivatives having a very specific substitution pattern, which should besuitable for the treatment of gastric and intestinal disorders, andcertain processes for their preparation. In the document Drugs Fut 2001,26 (6), 590, the preparation of tetrahydrobenzopyranes by cyclizatonusing ortho-esters is disclosed.

DESCRIPTION OF THE INVENTION

The invention relates to a new process for the production of thetricyclic imidazopyridine derivatives mentioned above, and to valuableintermediates used in said processes.

The invention thus relates in a first aspect to compounds of the formula1

-   R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl,    3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl,    1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl    or hydroxy-1-4C-alkyl,-   R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl,    3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl,    halogen, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, cyanomethyl-   R3a is hydrogen, halogen, fluoro-1-4C-alkyl, 1-4C-alkyl,    2-4C-alkenyl, 2-4C-alkynyl, carboxyl, 1-4C-alkoxycarbonyl,    hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl,    1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or    the radical —CO—NR31R32,-   R3b is hydrogen, halogen, fluoro-1-4C-alkyl, 1-4C-alkyl,    2-4C-alkenyl, 2-4C-alkynyl, carboxyl, 1-4C-alkoxycarbonyl,    hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl,    1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or    the radical —CO—NR31R32,    -   where    -   R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or        1-4C-alkoxy-1-4C-alkyl and    -   R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or        1-4C-alkoxy-1-4C-alkyl,    -   or where    -   R31 and R32 together, including the nitrogen atom to which both        are bonded, are a pyrrolidino, piperidino, piperazino,        N-1-4C-alkylpiperazino or morpholino radical,-   Arom is a mono- or bicyclic aromatic radical substituted by R4, R5,    R6 and R7, which is selected from the group consisting of phenyl,    naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl,    benzimidazolyl, furanyl (furyl), benzofuranyl (benzofuyl),    thiophenyl (thienyl), benzothiophenyl (benzothienyl), thiazolyl,    isoxazolyl, pyridinyl, pyrimidinyl, quinolinyl and isoquinolinyl,    -   where    -   R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy,        2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carbonyl,        1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl,        1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxyl, aryl,        aryl-1-4C-alkyl, aryloxy, aryl-1-4C-alkoxy, trifluoromethyl,        nitro, amino, mono- or di-1-4C-alkylamino,        1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino,        1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,    -   R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl,        halogen, trifluoromethyl or hydroxyl,    -   R6 is hydrogen, 1-4C-alkyl or halogen and    -   R7 is hydrogen, 1-4C-alkyl or halogen,    -   where    -   aryl is phenyl or substituted phenyl having one, two or three        identical or different substituents from the group consisting of        1-4C-alkyl, 1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl, halogen,        trifluoromethyl, nitro, trifluoromethoxy, hydroxyl and cyano,        and their salts.

1-4C-Alkyl represents straight-chain or branched alkyl radicals having 1to 4 carbon atoms. Examples which may be mentioned are the butyl,isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methylradical.

3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl andcyclopentyl are preferred.

3-7C-Cycloalkyl-1-4C-alkyl represents one of the aforementioned1-4C-alkyl radicals, which is substituted by one of the aforementioned3-7C-cycloalkyl radicals. Examples which may be mentioned are thecyclopropylmethyl, the cyclohexylethyl radical.

1-4C-Alkoxy represents radicals, which in addition to the oxygen atomcontain a straight-chain or branched alkyl radical having 1 to 4 carbonatoms. Examples which may be mentioned are the butoxy, isobutoxy,sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxyand methoxy radical.

1-4C-Alkloxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkylradicals, which is substituted by one of the aforementioned 1-4C-alkoxyradicals. Examples which may be mentioned are the methoxymethyl, themethoxyethyl radical and the butoxyethyl radical.

1-4C-Alkoxycarbonyl represents a carbonyl group, to which one of theaforementioned 1-4C-alkoxy radicals is bonded. Examples which may bementioned are the methoxycarbonyl (CH₃O—C(O)—) and the ethoxycarbonylradical (CH₃CH₂O—C(O)—).

2-4C-Alkenyl represents straight-chain or branched alkenyl radicalshaving 2 to 4 carbon atoms. Examples which may be mentioned are the2-butenyl, 3-butenyl, 1-propenyl and the 2-propenyl radical (allylradical).

2-4C-Alkynyl represents straight-chain or branched alkynyl radicalshaving 2 to 4 carbon atoms. Examples which may be mentioned are the2-butynyl, 3-butynyl, and preferably the 2-propynyl, radical (propargylradical).

Fluoro-1-4C-alkyl represents one of the aforementioned 1-4C-alkylradicals, which is substituted by one or more fluorine atoms. An examplewhich may be mentioned is the trifluoromethyl radical.

Hydroxy-1-4C-alkyl represents aforementioned 1-4C-alkyl radicals, whichare substituted by a hydroxy group. Examples which may be mentioned arethe hydroxymethyl, the 2-hydroxyethyl and the 3-hydroxypropyl radical.

Halogen within the meaning of the invention is bromo, chloro and fluoro.

1-4C-Alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxyradicals, which is substituted by a further 1-4C-alkoxy radical.Examples which may be mentioned are the radicals 2-(methoxy)ethoxy(CH₃—O—CH₂—CH₂—O—) and 2-(ethoxy)ethoxy (CH₃—CH₂—O—CH₂—CH₂—O—).

1-4C-Alkoxy-1-4C-alkoxy-1-4C-alkyl represents one of the aforementioned1-4C-alkoxyl1-4Calkyl radicals, which is substituted by one of theaforementioned 1-4C-alkoxy radicals. An example which may be mentionedis the radical 2-(methoxy)ethoxy-methyl (CH₃—O—CH₂—CH₂O—CH₂—).

Fluoro-1-4C-alkoxy-1-4C-alkyl represents one of the aforementioned1-4C-alkyl radicals, which is substituted by a fluoro-1-4C-alkoxyradical. Fluoro-1-4C-alkoxy in this case represents one of theaforementioned 1-4C-alkoxy radicals, which is wholly or mainlysubstituted by fluorine. Examples of wholly or mainly fluoro-substituted1-4C-alkoxy which may be mentioned are the1,1,1,3,3,3-hexafluoro-2-propoxy, the 2-trifluoromethyl-2-propoxy, the1,1,1-trifluoro-2-propoxy, the perfluoro-tert-butoxy, the2,2,3,3,4,4,4-heptafluoro-1-butoxy, the 4,4,4-trifluoro-1-butoxy, the2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the1,2,2-trifluoroethoxy, in particular the 1,1,2,2-tetrafluoroethoxy, the2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably thedifluoromethoxy radical.

1-7C-Alkyl denotes straight-chain or branched alkyl radicals having 1 to7 carbon atoms. Examples which may be mentioned are the heptyl,isoheptyl-(5-methylhexyl), hexyl, isohexyl-(4-methylpentyl),neohexyl-(3,3-dimethylbutyl), pentyl, isopentyl-(3-methylbutyl),neopentyl-(2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl,propyl, isopropyl, ethyl and methyl radicals.

2-4C-Alkenyloxy represents a radical, which in addition to the oxygenatom contains a 2-4C-alkenyl radical. An example which may be mentionedis the allyloxy radical.

1-4C-Alkylcarbonyl represents a radical, which in addition to thecarboyl group contains one of the aforementioned 1-4C-alkyl radicals. Anexample which may be mentioned is the acetyl radical.

Carboxy-1-4C-alkyl for example represents the carboxymethyl (—CH₂COOH)or the carboxyethyl radical (—CH₂CH₂COOH).

1-4C-Alkoxycarbonyl-1-4C-alkyl represents one of the aforementioned1-4C-alkyl radicals, which is substituted by one of the aforementioned1-4C-alkoxycarbonyl radicals. An example which may be mentioned is theethoxycarbonylmethyl radical (CH₃CH₂OC(O)CH₂—).

Aryl-1-4C-alkyl represents an aryl-substituted 1-4C-alkyl radical. Anexample which may be metnioned is the benzyl radical.

Aryl-1-4C-alkoxy represents an aryl-substituted 1-4C-alkoxy radical. Anexample which may be mentioned is the benzyloxy radical.

Mono- or di-1-4C-alkylamino radicals contain, in addition to thenitrogen atom, one or two of the aforementioned 1-4C-alkyl radicals.Di-1-4C-alkylamino is preferred and here, in particular, dimethyl-,diethyl- or dilsopropylamino.

1-4C-Alkylcarbonylamino represents an amino group to which a1-4C-alkylcarbonyl radical is bonded. Examples which may be mentionedare the propionylamino (C₃H₂C(O)NH—) and the acetylamino radical(acetamido radical) (CH₃C(O)NH—).

1-4C-Alkoxycarbonylamino represents an amino radical, which issubstituted by one of the aforementioned 1-4C-alkoxycarbonyl radicals.Examples which may be mentioned are the ethoxycarbonylamino and themethoxycarbonylamino radical.

1-4C-Alkoxy-1-4C-alkoxycarbonyl represents a carbonyl group, to whichone of the aforementioned 1-4C-alkoxy-1-4C-alkoxy radicals is bonded.Examples which may be mentioned are the 2-(methoxy)ethoxycarbonyl(CH₃—O—CH₂CH₂—O—CO—) and the 2-(ethoxy)ethoxy-carbonyl radical(CH₃CH₂—O—CH₂CH₂—O—CO—).

1-4C-Alkoxy-1-4C-alkoxycarbonylamino represents an amino radical, whichis substituted by one of the aforementioned1-4C-alkoxy-1-4C-alkoxycarbonyl radicals. Examples which may bementioned are the 2-(methoxy)ethoxycarbonylamino and the2-(ethoxy)ethoxycarbonyl-amino radical.

Arom radicals which may be mentioned are, for example, the followingsubstituents: 4-acetoxyphenyl, 4-acetamidophenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 3-benzyloxyphenyl, 4-benzyloxyphenyl,3-benzyloxy-4-methoxyphenyl, 4-benzyloxy-3-methoxyphenyl,3,5-bis(trifluoromethyl)phenyl, 4-butoxyphenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 2-chloro-6-fluorophenyl,3-chloro-4-fluorophenyl, 2-chloro-5-nitrophenyl, 4-chloro-3-nitrophenyl,3-(4-chlorophenoxy)phenyl, 2,4-dichlorophenyl, 3,4-difluorophenyl,2,4-dihydroxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxy-5-hydroxyphenyl,2,5-dimethylphenyl, 3-ethoxy-4-hydroxyphenyl, 2-fluorophenyl,4-fluorophenyl, 4-hydroxyphenyl, 2-hydroxy-5-nitrophenyl,3-methoxy-2-nitrophenyl, 3-nitrophenyl, 2,3,5-trichlorphenyl,2,4,6-trihydroxyphenyl, 2,3,4-trimethoxyphenyl, 2-hydroxy-1-naphthyl,2-methoxy-1-naphthyl, 4-methoxy-1-naphthyl, 1-methyl-2-pyrrolyl,2-pyrrolyl, 3-methyl-2-pyrroly, 3,4-dimethyl-2-pyrrolyl,4-(2-methoxycarbonylethyl)-3-methyl-2-pyrrolyl,5-ethoxycarbonyl-2,4-dimethyl-3-pyrrolyl,3,4-dibromo-5-methyl-2-pyrrolyl, 2,5-dimethyl-1-phenyl-3-pyrrolyl,5-carboxy-3-ethyl-4-methyl-2-pyrrolyl, 3,5-dimethyl-2-pyrrolyl,2,5-dimethyl-1-(4-trifluormethylphenyl)-3-pyrrolyl,1-(2,6-dichloro-4-trifluoromethylphenyl)-2-pyrrolyl,1-(2-nitrobenzyl)-2-pyrrolyl, 1-(2-fluorophenyl)-2-pyrrolyl,1-(4-trifluoromethoxyphenyl)-2-pyrrodyl, 1-(2-nitrobenzyl)-2-pyrrolyl,1-(4-ethoxycarbonyl)-2,5-dimethyl-3-pyrrolyl,5-chloro-1,3-dimethyl-4-pyrazolyl,5-chloro-1-methyl-3-trifluoromethyl-4-pyrazolyl,1-(4-chlorobenzyl)-5-pyrazolyl,1,3-dimethyl-5-(4-chlorphenoxy)-4-pyrazolyl,1-methyl-3-trifluomethyl-5-(3-trifluoromethylphenoxy)-4-pyrazolyl,4-methoxycarbonyl-1-(2,6-dichlorophenyl)-5-pyrazolyl,5-allyloxy-1-methyl-3-trifluoromethyl-4-pyrazolyl,5-chloro-1-phenyl-3-trifluoromethyl-4-pyrazolyl,3,5-dimethyl-1-phenyl-4-imidazolyl, 4-bromo-1-methyl-5-imidazolyl,2-butylmidazolyl, 1-phenyl-1,2,3-triazol-4-yl, 3-indolyl, 4-indolyl,7-indolyl, 5-methoxy-3-indolyl, 5-benzyloxy-3-indolyl,1-benzyl-3-indolyl, 2-(4-chlorophenyl)-3-indolyl, 7-benzyloxy-3-indolyl,6-benzyloxy-3-indolyl, 2-methyl-5-nitro-3-indolyl,4,5,6,7-tetrafluoro-3-indolyl, 1-(3,5-difluorobenzyl)-3-indolyl,1-methyl-2-(4-trifluorophenoxy)-3-indolyl, 1-methyl-2-benzimidazolyl,5-nitro-2-furyl, 5-hydroxymethyl-2-furyl, 2-furyl, 3-furyl,5-(2-nitro-4-trifluoromethylphenyl)-2-furyl,4-ethoxycarbonyl-5-methyl-2-furyl, 5-(2-trifluromethoxyphenyl)-2-furyl,5-(4-methoxy-2-nitrophenyl)-2-furyl, 4-bromo-2-furyl,5-dimethylamino-2-furyl, 5-bromo-2-furyl, 5-sulfo-2-furyl, 2-benzofuryl,2-thienyl, 3-thienyl, 3-methyl-2-thienyl, 4-bromo-2-thienyl,5-bromo-2-thienyl, 5-nitro-2-thienyl, 5-methyl-2-thienyl,5-(4-methoxyphenyl)-2-thienyl, 4-methyl-2-thienyl, 3-phenoxy-2-thienyl,5-carboxy-2-thienyl, 2,5-dichloro-3-thienyl, 3-methoxy-2-thienyl,2-benzothianyl, 3-methyl-2-benzothienyl,2-bromo-5-chloro-3-benzothienyl, 2-thiazolyl,2-amino-4-chloro-5-thiazolyl, 2,4-dichloro-5-thiazolyl,2-diethylamino-5-thiazolyl, 3-methyl-4-nitro-5-isoxazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 6-methyl-2-pyridyl,3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridyl, 2,6-dichloro-4-pyridyl,3-chloro-5-trifluoromethyl-2-pyridyl, 4,6-dimethyl-2-pyridyl,4-(4-chlorphenyl)-3-pyridyl,2-chloro-5-methoxycarbonyl-6-methyl-4-phenyl-3-pyridyl,2-chloro-3-pyridyl, 6-(3-trifluoromethylphenoxy)-3-pyridyl,2-(4-chlorophenoxy)-3-pyridyl, 2,4-dimethoxy-5-pyrimidinyl,2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 2-chloro-3-quinolinyl,2-chloro-6-methoxy-3-quinolinyl, 8-hydroxyl-2-quinolinyl and4-isoquinolinyl.

Possible salts of compounds of the formula I—depending onsubstitution—are especially all acid addition salts. Particular mentionmay be made of the pharmacologically tolerable salts of the inorganicand organic acids customarily used in pharmacy. Those suitable arewater-soluble and water-insoluble acid addition salts with acids suchas, for example, hydrochloric acid, hydrobromic acid, phosphoric acid,nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid,benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid,sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid,succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid,toluensulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid,where the acids are used in salt preparation—depending on whether amono- or polybasic acid is concerned and on which salt is desired—in anequimolar quantitative ratio or one differing therefrom.

It is known to the person skilled in the art that the compoundsaccording to invention and their salts, if, for example, they areisolated in crystalline form, can contain various amounts of solvents.The invention therefore also comprises all solvates and in particularall hydrates of the compounds of the formula I, and also all solvatesand in particular all hydrates of the salts of the compounds of theformula I.

The compounds of the formula 1 have two chiral centers in the parentstructure. The invention thus relates to all conceivable stereoisomersin any desired mixing ratio to one another, including the pureenanitomers, which are a preferred subject of the invention.

One embodiment (embodiment 1) of the invention are compounds of theformula 1, in which

-   R1 is 1-4C-alkyl and-   R2, R3a, R3b and Arom have the meanings as described in the outset.

Another embodiment (embodiment 2) of the invention are compounds of theformula 1, in which

-   R2 is 1-4C-alkyl and-   R1, R3a, R3b and Arom have the meanings as described in the outset.

Another embodiment (embodiment 3) of the invention are compounds of theformula 1, in which

-   R3a is hydrogen and-   R1, R2, R3b and arom have the meanings as described in the outset.

Another embodiment (embodiment 4) of the invention are compounds of theformula 1, in which

-   R3b is hydrogen and-   R1, R2, R3a and Arom have the meanings as described in the outset.

Another embodiment (embodiment 5) of the invention are compounds of theformula 1, in which

-   Arom is phenyl and-   R1, R2, R3a and R3b have the meanings as described in the outset.

Compounds to be emphasized are those of the formula 1, in which

-   R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkoxy-1-4C-alkyl,    2-4C-alkynyl or fluoro-1-4C-alkyl,-   R2 is hydrogen, 1-4C-alkyl, aryl, hydroxy-1-4C-alkyl, halogen,    2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl-   R3a is hydrogen,-   R3b is hydrogen, halogen, 1-4C-alkyl or the radical-CO—31R32,    -   where    -   R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or        1-4C-alkoxy-1-4C-alkyl and    -   R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or        1-4C-alkoxy-1-4C-alkyl,    -   or where    -   R31 and R32 together, including the nitrogen atom to which both        are bonded, are a pyrrolidino, piperidino or morpholino radical,-   Arom is a monocyclic aromatic radical substituted by R4, R5, R6 and    R7, which is selected from the group consisting of phenyl, furanyl    (furyl) and thiophenyl (thienyl),    -   where    -   R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy,        1-4C-alkylcarbonyl, carboxyl, 1-4C-alkoxycarbonyl, halogen,        hydroxyl, trifluoromethyl, 1-4C-alkylcarbonylamino,        1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino        or sulfonyl,    -   R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl,        halogen, trifluoromethyl or hydroxyl,    -   R6 is hydrogen and    -   R7 is hydrogen,        and their salts.

Compounds to be particularly emphasized are those of the formula 1, inwhich

-   R1 is 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,-   R2 is hydrogen, 1-4C-alkyl, phenyl, hydroxy-1-4C-alkyl or halogen-   R3a is hydrogen,-   R3b is hydrogen,-   Arom is phenyl, furanyl (furyl) or thiophenyl (thienyl),    and their salts.

Among the compounds according to the invention, including theembodiments 1 to 5 and the compounds to be emphasized and to beparticularly emphasized, the optically pure compounds of the formula 1*

are preferred.

Preferred compounds of the formula 1* are those in which

-   R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkoxy-1-4C-alkyl,    2-4C-alkynyl or fluoro-1-4C-alkyl,-   R2 is hydrogen, 1-4C-alkyl, aryl, hydroxy-1-4C-alkyl, halogen,    2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl-   R3a is hydrogen,-   R3b is hydrogen, halogen, 1-4C-alkyl or the radical —CO—NR31R32.    -   where    -   R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or        1-4C-alkoxy-1-4C-alkyl and    -   R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or        1-4C-alkoxy-1-4C-alkyl,    -   or where-   R31 and R32 together, including the nitrogen atom to which both are    bonded, are a pyrrolidine, piperidino or morpholino radical-   Arom is phenyl, furanyl (furyl) or thiophenyl (thienyl),    and their salts.

Compounds with exemplary substituents to be particularly emphasized arethose of the formula 1*, in which

-   R1 is hydrogen, methyl, cyclopropyl, methoxymethyl or    trifluoromethyl,-   R2 is hydrogen, methyl, phenyl, hydroxymethyl, fluoro, chloro,    bromo, ethynyl, trifluomethyl-   R3a is hydrogen,-   R3b is hydrogen, fluorine, methyl or the radical —CO—N(CH₃)₂,-   Arom is a phenyl radical    and their salts.

Particularly preferred exemplary compounds of the formula 1* are those,in which

-   R1 is methyl,-   R2 is hydrogen, methyl, fluoro, chloro, bromo, hydroxymethyl or    trifluoromethyl-   R3a is hydrogen,-   R3b is hydrogen,-   Arom is a phenyl radical    and their salts.

Particularly preferred are the compounds given as final products in theexamples, and their salts.

The invention further relates to the use of compounds of the formula 1,in which R1, R2, R3a, R3b and Arom have the meanings indicated in theoutset, for the preparation of compounds of the formula 2

in which R1, R2, R3, R3b and Arom have the meanings indicated in theoutset, and R8 is hydrogen, 1-4C-Alkyl or aryl, as indicated in theoutset, and their salts.

The preparation of the compounds of the formula 2 is effected, as shownfor example in scheme 1, such that the compounds of the formula 1, inwhich R1, R2, R3a, R3b and Arom have the meanings indicated in theoutset, are reacted with ortho-esters R8-C(OR9)₃, in which R8 ishydrogen, 1-4C-Alkyl or aryl, as indicated in the outset, and R9 is1-4C-alkyl.

To be emphasized according to the invention is the use of compounds ofthe formula 1* for the preparation of compounds of the formula 2*,

in which R1, R2, R3a, R3b and Arom have the meanings indicated in theoutset and R8 has the meaning hydrogen, 1-4C-Alkyl or aryl, as indicatedin the outset, and their salts.

The conversion of a compound of the formula 1 into a cyclization productof the formula 2 according to scheme 1 is carried out in a manner knownto the expert, e.g. similar to that disclosed in Drugs Fut 2001, 26 (6),590.

The compounds of the formula 1 according to the invention, in which R1,R2, R3a, R3b and Arom have the meanings indicated in the outset, can beprepared from the compounds of the formula 3, in which R1, R2, R3a, R3band Arom have the meanings indicated in the outset,

as shown by way of example in scheme 2 below for the compounds 1* and3*, by reaction with a mineral acid:

Preferred mineral acids for the reaction shown in scheme 2 arephosphoric acid, hydrochloric acid or sulphuric acid.

Starting compounds of the formula 3 are known (see WO01/72755 or WO02/34749) or they can be prepared in a known manner in analogy to knowncompounds as shown by way of example for the compound 3* in scheme 3below.

The group X in scheme 3 is a suitable leaving group, for example ahalogen atom, preferably chlorine, or a 1-4C alkoxy group, preferablymethoxy.

The following examples serve to explain the invention in greater detailwithout restricting it. Likewise, further compounds of the formula 1,whose preparation is not described explicity, can be prepared in ananalogous manner or in a manner familiar per set to the person skilledin the art using customary process techniques. The abbreviation minstands for minute(s), h for hour(s) and m. p. for melting point.

EXAMPLES Compounds of the Formula 1 1.2-Methyl-7-[(2R,3S)-2,3-diyhdroxy-3-phenylpropan-1-on-1-yl]imidazo[1,2-a]-pyridin-8-ol

156 g (0.442 mol) of2-Methyl-7-[(2R,3S)-2,3-O,O-isopropylidan-2,3-dioxy-3-phenylpropan-1-on-1-yl]-imidazo[1,2-a]-pyridin-8-olare dissolved in 3 l of 6 molar hydrochloric acid during 30 min. Afterstirring for 1 h at room temperature, the reaction mixture is cooledwith an ice bath and neutralized to pH 6.5 to 7 using a 6 molar sodiumhydroxide solution. The precipitate is filtered off, washed with waterand for the most part redissolved in 0.5 molar hydrochloric acid. Theremaining residue is separated by filtration and the filtrate isneutralized again to pH 6.5 to 7 using a 6 molar sodium hydroxidesolution. The resulting precipitate is filtered off and dried in vacuumto afford 84.6 g (0.271 mol, yield 61%) of the title compound inanalytical pure quality as a beige-brown solid.

m. p.: 110-115° C. (water)

2.2,3-Dimethyl-7-[(2R,3S)-2,3-diyhdroxy-3-phenylpropan-1-on-1-yl]imidazo[1,2-a]-pyridin-8-ol

10 g (0.027 mol) of2,3-Dimethyl-7-[(2R,3S)-2,3-O,O-isopropyliden-2,3-dioxy-3-phenylpropan-1-on-1-yl]-imidazo[1,2,-a]-pyridin-8-olare dissolved in 0 ml of 6 molar hydrochloric acid. After stirring for30 min at room temperature, the reaction mixture is cooled with an icebath and neutralized to pH 6.5 using a 6 molar sodium hydroxidesolution. The resulting residue is filtered off, washed with water anddried in vacuum at 55° C. The crude product is purified bychromatography on silica gel (eluent dichloromethane/methanol: 5/1) togive 5.77 g (0.018 mol, yield 65%) of the title compound as ochrecrystals.

¹H-NMR (CDCl₃): (ppm)=2.25 (3H, s), 2.38 (3H, s), 5.32 (1H, d), 5.55(1H, d), 7.13 (1H, d), 7.18-7.25 (3H, m), 7.51 (2H, dd), 7.70 (1H, d).

Use of Compounds of the Formula 1 According to the Invention for thePreparation of Compounds of the Formula 2

A.(8R,9R)-8-Acetoxy-2-methyl-9-phenyl-7H-8,9-dihydro-pyrano[2,3-c]imidazo[1,2-a]-pyridin-7-on

150 ml (1.166 mol) of orthoacetic acid trimethyl ester, 7.5 g (0.030mol) of pyridrium-p-toluenesulfonate and 13.5 ml (0.358 mol) of formicacid are added at room temperature to a solution of 93.4 g (0.299 mol)of2-Methyl-7-[(2R,3S)-2,3-diyhdroxy-3-phenylpropan-1-on-1-yl]imidazo-[1,2-a]-pyridin-8-olin 2.3 l of dichloromethane. After 2 h stirring at room temperature thereaction mixture is poured onto 1.5 l of a 0.25 molar sodium bicarbonatesolution. After 15 min stirring at room temperature the organic phase isseparated and the sequence phase extracted with methylene chloride. Thecombined organic layers are washed with saturated sodium bicarbonatesolution, dried over sodium sulphate and the solvent removed undervacuum. The resulting solid is recrystalized from diisopropyl ether anddried in vacuum to afford 91.3 g (0.271 mol, yield 90.8%) of the titlecompound in form of lightly yellow crystals.

m. p.: 220-222° C. (diisopropyl ether)

B.(8R,9R)-8-Acetoxy-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrano[2,3-c]imidazo[1,2-a]-pyridin-7-on

3.18 ml (0.025 mol) of orthoacetic acid trimethyl ester, 0.16 g (0.0008mol) of pyridinium-p-toluenesulfonate and 0.28 ml (0.007 mol) of formicacid are added at room temperature to a solution of 2 g (0.006 mol) of2,3-dimethyl-7-[(2R,3S)-2,3-dihydroxy-3-phenylpropan-1-on-1-yl]imidazo-[1,2-a]-pyridin-8-olin 40 ml of dichloromethane. After stirring for 16 h at roomtemperature, the reaction mixture is diluted with dichloromethane,washed with saturated sodium bicarbonate solution, dried over sodiumsulphate and the solvent removed under vacuum. The crude product ispurified by filtration over a thin layer of silica gel (solventdichloromethane/methanol: 100/1). After removal of the solvent, 1.8 g(0.005 mol, yield 84%) of the title compound is obtained in form ofcolourless crystals.

m. p.: 205-206° C. (diethyl ether/acetone).

C.(8R,9R)-2,3-Dimethyl-8-isobutyryloxy-9-phenyl-7H-8,9-dihydro-pyrano[2,3-c]imidazo-[1,2-a]pyridin-7-on

1.81 g (0.012 mol) of ortholsobutyric acid trimethyl ester, 0.08 g(0.0003 mol) of pyridinium-p-toluenesulfonate and 0.14 ml (0.004 mol) offormic acid are added at room temperature to a solution of 1 g (0.003mol) of2,3-dimethyl-7-[(2R,3S)-2,3-dihydroxy-3-phenylpropan-1-on-1-yl]imidazo-[1,2-a]-pyridin-8-olin 10 ml of dichloromethane. After stirring for 16 h at roomtemperature, the reaction mixture is poured onto a saturated sodiumbicarbonate solution, the aqueous layer extracted with dichloromethane,the combined organic layers dried over sodium sulphate and the solventremoved under vacuum. The crude product is purified by chromatography onsilica gel (eluent dichloromethane/methanol: 100/3) to give 0.98 g(0.003 mol, yield 85%) of the title compound in form of colourlesscrystals.

m. p.: 207-208° C. (acetone).

Conmercial Utility

The compounds of the formula 1 and their salts are valuableintermediates for the preparation of active compounds, such as aredisclosed, for example, in the international patent applications WO98/54188, WO 01/72756, WO 01/72754, WO 01/72757, WO 02/34749, WO03/016310, WO 03/014120 and WO 03/014123.

1. A compound of the formula 1

in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl,3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl,1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl orhydroxy-1-4C-alkyl, R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl,3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl,halogen, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, cyanomethyl, R3ais hydrogen, halogen, fluoro-1-4C-alkyl, 1-4C-alkyl, 2-4C-alkenyl,2-4C-alkynyl, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl,1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl,fluoro-1-4C-alkoxy-1-4C-alkyl or the radical —CO—NR31R32, R3b ishydrogen, halogen, fluoro-1-4C-alkyl, 1-4C-alkyl, 2-4C-alkenyl,2-4C-alkynyl, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl,1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl,fluoro-1-4C-alkoxy-1-4C-alkyl or the radical —CO—NR31R32, where R31 ishydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl andR32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including thenitrogen atom to which both are bonded, are a pyrrolidino, piperidino,piperazino, N-1-4C-alkylpiperazino or morpholino radical, Arom is amono- or bicyclic aromatic radical substituted by R4, R5, R6 and R7,which is selected from the group consisting of phenyl, naphthyl,pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl,benzimidazolyl, furanyl (furyl), benzofuranyl (benzofuryl), thiophenyl(thienyl), benzothiophenyl (benzothienyl), thiazolyl, isoxazolyl,pyridinyl, pyrimidinyl, quinolinyl and isoquinolinyl, where R4 ishydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy,1-4C-alkylcarbonyl, carboxyl, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl,1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxyl, aryl,aryl-1-4C-alkyl, aryloxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro,amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino,1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino orsulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl,halogen, trifluoromethyl or hydroxyl, R6 is hydrogen, 1-4C-alkyl orhalogen and R7 is hydrogen, 1-4C-alkyl or halogen, where aryl is phenylor substituted phenyl having one, two or three identical or differentsubstituents selected from the group consisting of 1-4C-alkyl,1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl,nitro, trifluoromethoxy, hydroxyl and cyano, or a salt, thereof.
 2. Acompound of the formula 1 according to claim 1, in which R1 is hydrogen,1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkoxy-1-4C-alkyl, 2-4C-alkynyl orfluoro-1-4C-alkyl, R2 is hydrogen, 1-4C-alkyl, aryl, hydroxy-1-4C-alkyl,halogen, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, R3a is hydrogen,R3b is hydrogen, halogen, 1-4C-alkyl or the radical —CO—NR31R32, whereR31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or1-4C-alkoxy-1-4C-alkyl and R32 is hydrogen, 1-7C-alkyl,hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32together, including the nitrogen atom to which both are bonded, are apyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino ormorpholino radical, Arom is a monocyclic aromatic radical substituted byR4, R5, R6 and R7, which is selected from the group consisting ofphenyl, furanyl (furyl) and thiophenyl (thienyl), where R4 is hydrogen,1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylcarbonyl,carboxyl, 1-4C-alkoxycarbonyl, halogen, hydroxyl, trifluoromethyl,1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino,1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen,1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethylor hydroxyl, R6 is hydrogen and R7 is hydrogen, or a salt, thereof.
 3. Acompound of the formula 1 according to claim 1, in which R1 is1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, R2 is hydrogen, 1-4C-alkyl,phenyl, hydroxy-1-4C-alkyl, halogen, R3a is hydrogen, R3b is hydrogen,Arom is phenyl, furanyl (furyl) or thiophenyl (thienyl), or a salt,thereof.
 4. A compound according to claim 1, characterized by thegeneral formula 1*,

in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl,1-4C-alkoxy-1-4C-alkyl, 2-4C-alkynyl or fluoro-1-4C-alkyl, R2 ishydrogen, 1-4C-alkyl, aryl, hydroxy-1-4C-alkyl, halogen, 2-4C-alkenyl,2-4C-alkynyl, fluoro-1-4C-alkyl, R3a is hydrogen, R3b is hydrogen,halogen, 1-4C-alkyl or the radical —CO—NR31R32, where R31 is hydrogen,1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and R32 ishydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, orwhere R31 and R32 together, including the nitrogen atom to which bothare bonded, are a pyrrolidino, piperidino or morpholino radical, Arom isphenyl, furanyl (furyl) or thiophenyl (thienyl), or salt, thereof.
 5. Acompound according to claim 1, characterized by formula 1*

in which R1 is hydrogen, methyl, cyclopropyl, methoxymethyl ortrifluoromethyl, R2 is hydrogen, methyl, phenyl, hydroxymethyl, chloro,bromo, ethynyl, trifluoromethyl, R3a is hydrogen, R3b is hydrogen,fluorine, methyl or the radical —CO—N (CH₃)₂, Arom is a phenyl radical,or a salt, thereof.
 6. A compound according to claim 1, characterized byformula 1*

in which R1 is methyl, R2 is hydrogen, methyl, fluoro, chloro, bromo,hydroxymethyl or trifluoromethyl, R3a is hydrogen, R3b is hydrogen, Aromis a phenyl radical, or a salt, thereof.
 7. A process of preparing acompound of the formula 2 or a salt, thereof,

in which R1, R2, R3a, R3b and Arom have the meanings indicated in claim1, and R8 is hydrogen, 1-4C-Alkyl or aryl, where aryl has the meaning asindicated in claim 1, comprising reacting a compound of the formula 1

or a hydrate, solvate, salt, hydrate of a salt or solvate of a saltthereof, in which R1, R2, R3a, R3b and Arom have the meanings indicatedin claim 1, with an ortho-ester of the formula R8-C(OR9)₃, in which R8is hydrogen, 1-4C-Alkyl or aryl, wherein aryl has the meanings indicatedin claim 1, and R9 is 1-4C-alkyl.
 8. A process of preparing a compoundof the formula 2* or a salt, thereof,

in which R1, R2, R3a, R3b and Arom have the meanings indicated in claim4, and R8 is hydrogen, 1-4C-Alkyl or aryl, where aryl is phenyl orsubstituted phenyl having one, two or three identical or differentsubstituents selected from the group consisting of 1-4C-alkyl,1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl,nitro, trifluoromethoxy, hydroxyl and cyano, comprising reacting acompound of the formula 1*

or a hydrate, solvate, salt, hydrate of a salt or solvate of a saltthereof, in which R1, R2, R3a, R3b and Arom have the meanings indicatedin claim 4, with an ortho-ester of the formula R8-C(OR9)₃, in which R8is hydrogen, 1-4C-Alkyl or aryl, wherein aryl has the meanings indicatedabove, and R9 is 1-4C-alkyl.
 9. A process for the preparation of acompound of the formula 1 as claimed in claim 1, in which R1, R2, R3a,R3b and Arom have the meanings indicated in claim 1, which comprisesdeprotection of a compound of the formula 3,

in which R1, R2, R3a, R3b and Arom have the meanings indicated in claim1, by reacting said compound with a mineral acid.
 10. A process for thepreparation of a compound of the formula 1* as claimed in claim 4, inwhich R1, R2, R3a, R3b and Arom have the meanings indicated in claim 4,which comprises deprotection of a compound of the formula 3*,

in which R1, R2, R3a, R3b and Arom have the meanings indicated in claim4, by reacting said compound with a mineral acid.